Comparing Two Medical Treatments for Early Pregnancy Failure.

Summary

This study aims to compare whether a combination of two drugs (Mifepristone and misoprostol) are superior compared to using only one of these drugs (Misoprostol) as medical treatment for a miscarriage. Women in whom early pregnancy failure, 6-14 weeks postmenstrual, is ultrasonographically confirmed qualify for this study. It is expected that the combination of Mifepristone and Misoprostol is more effective in reaching complete evacuation, and therefore can prevent more invasive treatment such as curettage.

Timeline

Start

2018-06-27

Primary completion

2020-01-23

Completion

2020-03-16

Outcome

Met primary endpoint

Stopped: “Advised by DSMB based on interim-analysis, highly significant difference.”

paper 136 (79•1%) of 172 participants reached complete evacuation compared to 101 (58•7%) of 172 participants in the placebo group (p<0•0001, RR 1•35, 95% CI 1•16-1•56). PMID 33681738 ↗

paper INTERPRETATION: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL. PMID 33681738 ↗

Publications

• Background Graziosi GC, Mol BW, Reuwer PJ, Drogtrop A, Bruinse HW. Misoprostol versus curettage in women with early pregnancy failure after initial expectant management: a randomized trial. Hum Reprod. 2004 Aug;19(8):1894-9. doi: 10.1093/humrep/deh344. Epub 2004 Jun 10.
• Background You JH, Chung TK. Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod. 2005 Oct;20(10):2873-8. doi: 10.1093/humrep/dei163. Epub 2005 Jun 24.
• Background Hooker AB, Lemmers M, Thurkow AL, Heymans MW, Opmeer BC, Brolmann HA, Mol BW, Huirne JA. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update. 2014 Mar-Apr;20(2):262-78. doi: 10.1093/humupd/dmt045. Epub 2013 Sep 29.
• Background Lemmers M, Verschoor MA, Hooker AB, Opmeer BC, Limpens J, Huirne JA, Ankum WM, Mol BW. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum Reprod. 2016 Jan;31(1):34-45. doi: 10.1093/humrep/dev274. Epub 2015 Nov 2.
• Background Soulat C, Gelly M. [Immediate complications of surgical abortion]. J Gynecol Obstet Biol Reprod (Paris). 2006 Apr;35(2):157-62. doi: 10.1016/s0368-2315(06)76389-x. French.
• Background Niinimaki M, Jouppila P, Martikainen H, Talvensaari-Mattila A. A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. Fertil Steril. 2006 Aug;86(2):367-72. doi: 10.1016/j.fertnstert.2005.12.072. Epub 2006 Jun 9.
• Background Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006 Jul 19;2006(3):CD002253. doi: 10.1002/14651858.CD002253.pub3.
• Background van den Berg J, Gordon BBM, Snijders MPML, Vandenbussche FPHA, Coppus SFPJ. The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: a systematic review of the literature. Eur J Obstet Gynecol Reprod Biol. 2015 Dec;195:18-26. doi: 10.1016/j.ejogrb.2015.09.027. Epub 2015 Sep 30.
• Background Lemmers M, Verschoor MAC, Oude Rengerink K, Naaktgeboren C, Bossuyt PM, Huirne JAF, Janssen IAH, Radder C, Klinkert ER, Langenveld J, van der Voet L, Siemens FF, Bongers MY, van Hooff MH, van der Ploeg M, Sjors FPJ, Coppus SFPJ, Ankum WM, Mol BWJ; MisoREST study group. MisoREST: Surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: A cohort study. Eur J Obstet Gynecol Reprod Biol. 2017 Apr;211:83-89. doi: 10.1016/j.ejogrb.2017.01.019. Epub 2017 Jan 27.
• Background Lemmers M, Verschoor MA, Oude Rengerink K, Naaktgeboren C, Opmeer BC, Bossuyt PM, Huirne JA, Janssen CA, Radder C, Klinkert ER, Langenveld J, Catshoek R, Van der Voet L, Siemens F, Geomini P, Van Hooff MH, Van der Ploeg JM, Coppus SF, Ankum WM, Mol BW; MisoREST study group. MisoREST: surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: a randomized controlled trial. Hum Reprod. 2016 Nov;31(11):2421-2427. doi: 10.1093/humrep/dew221. Epub 2016 Sep 2.
• Background Say L, Kulier R, Gulmezoglu M, Campana A. Medical versus surgical methods for first trimester termination of pregnancy. Cochrane Database Syst Rev. 2005 Jan 25;2002(1):CD003037. doi: 10.1002/14651858.CD003037.pub2.
• Background Kulier R, Kapp N, Gulmezoglu AM, Hofmeyr GJ, Cheng L, Campana A. Medical methods for first trimester abortion. Cochrane Database Syst Rev. 2011 Nov 9;2011(11):CD002855. doi: 10.1002/14651858.CD002855.pub4.
• Background Maria B, Chaneac M, Stampf F, Ulmann A. [Early pregnancy interruption using an antiprogesterone steroid: Mifepristone (RU 486)]. J Gynecol Obstet Biol Reprod (Paris). 1988;17(8):1089-94. French.
• Background Grimes DA, Mishell DR Jr, Shoupe D, Lacarra M. Early abortion with a single dose of the antiprogestin RU-486. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 1):1307-12. doi: 10.1016/0002-9378(88)90361-4.
• Background van den Berg J, van den Bent JM, Snijders MP, de Heus R, Coppus SF, Vandenbussche FP. Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: a retrospective study. Eur J Obstet Gynecol Reprod Biol. 2014 Dec;183:16-9. doi: 10.1016/j.ejogrb.2014.10.010. Epub 2014 Oct 14.
• Background Stockheim D, Machtinger R, Wiser A, Dulitzky M, Soriano D, Goldenberg M, Schiff E, Seidman DS. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril. 2006 Oct;86(4):956-60. doi: 10.1016/j.fertnstert.2006.03.032.
• Background Wagaarachchi PT, Ashok PW, Narvekar N, Smith NC, Templeton A. Medical management of early fetal demise using a combination of mifepristone and misoprostol. Hum Reprod. 2001 Sep;16(9):1849-53. doi: 10.1093/humrep/16.9.1849.
• Background Gronlund A, Gronlund L, Clevin L, Andersen B, Palmgren N, Lidegaard O. Management of missed abortion: comparison of medical treatment with either mifepristone + misoprostol or misoprostol alone with surgical evacuation. A multi-center trial in Copenhagen county, Denmark. Acta Obstet Gynecol Scand. 2002 Nov;81(11):1060-5.
• Background Coughlin LB, Roberts D, Haddad NG, Long A. Medical management of first trimester miscarriage (blighted ovum and missed abortion): is it effective? J Obstet Gynaecol. 2004 Jan;24(1):69-71. doi: 10.1080/01443610310001620332.
• Background Schreiber CA, Creinin MD, Reeves MF, Harwood BJ. Mifepristone and misoprostol for the treatment of early pregnancy failure: a pilot clinical trial. Contraception. 2006 Dec;74(6):458-62. doi: 10.1016/j.contraception.2006.07.007. Epub 2006 Sep 7.
• Background Kollitz KM, Meyn LA, Lohr PA, Creinin MD. Mifepristone and misoprostol for early pregnancy failure: a cohort analysis. Am J Obstet Gynecol. 2011 May;204(5):386.e1-6. doi: 10.1016/j.ajog.2010.12.026. Epub 2011 Feb 8.
• Background Torre A, Huchon C, Bussieres L, Machevin E, Camus E, Fauconnier A. Immediate versus delayed medical treatment for first-trimester miscarriage: a randomized trial. Am J Obstet Gynecol. 2012 Mar;206(3):215.e1-6. doi: 10.1016/j.ajog.2011.12.009. Epub 2011 Dec 16.
• Background Luise C, Jermy K, May C, Costello G, Collins WP, Bourne TH. Outcome of expectant management of spontaneous first trimester miscarriage: observational study. BMJ. 2002 Apr 13;324(7342):873-5. doi: 10.1136/bmj.324.7342.873.
• Background Rulin MC, Bornstein SG, Campbell JD. The reliability of ultrasonography in the management of spontaneous abortion, clinically thought to be complete: a prospective study. Am J Obstet Gynecol. 1993 Jan;168(1 Pt 1):12-5. doi: 10.1016/s0002-9378(12)90877-7.
• Background Creinin MD, Harwood B, Guido RS, Fox MC, Zhang J; NICHD Management of Early Pregnancy Failure Trial. Endometrial thickness after misoprostol use for early pregnancy failure. Int J Gynaecol Obstet. 2004 Jul;86(1):22-6. doi: 10.1016/j.ijgo.2004.02.004.
• Background Chung TK, Cheung LP, Sahota DS, Haines CJ, Chang AM. Evaluation of the accuracy of transvaginal sonography for the assessment of retained products of conception after spontaneous abortion. Gynecol Obstet Invest. 1998;45(3):190-3. doi: 10.1159/000009954.
• Background Jauniaux E, Johns J, Burton GJ. The role of ultrasound imaging in diagnosing and investigating early pregnancy failure. Ultrasound Obstet Gynecol. 2005 Jun;25(6):613-24. doi: 10.1002/uog.1892.
• Background Verschoor MA, Lemmers M, Wekker MZ, Huirne JA, Goddijn M, Mol BW, Ankum WM. Practice variation in the management of first trimester miscarriage in the Netherlands: a nationwide survey. Obstet Gynecol Int. 2014;2014:387860. doi: 10.1155/2014/387860. Epub 2014 Nov 4.
• Hamel CC, Vart P, Vandenbussche FPHA, Braat DDM, Snijders MPLM, Coppus SFPJ. Predicting the likelihood of successful medical treatment of early pregnancy loss: development and internal validation of a clinical prediction model. Hum Reprod. 2022 May 3;37(5):936-946. doi: 10.1093/humrep/deac048.
• Hamel C, Coppus S, van den Berg J, Hink E, van Seeters J, van Kesteren P, Merien A, Torrenga B, van de Laar R, Terwisscha van Scheltinga J, Gaugler-Senden I, Graziosi P, van Rumste M, Nelissen E, Vandenbussche F, Snijders M. Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M trial): A double-blind placebo-controlled randomised trial. EClinicalMedicine. 2021 Jan 6;32:100716. doi: 10.1016/j.eclinm.2020.100716. eCollection 2021 Feb.
• van den Berg J, Hamel CC, Snijders MP, Coppus SF, Vandenbussche FP. Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: study protocol for a randomized double blinded placebo-controlled comparison (Triple M Trial). BMC Pregnancy Childbirth. 2019 Nov 27;19(1):443. doi: 10.1186/s12884-019-2497-y.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Mifepristone	Small molecule	600 mg	Oral
Background	Misoprostol	Other / unclassified	800 ug	Oral

Indications